Gene Expression Signatures Reveal Common Virus Infection Pathways in Target Tissues of Type 1 Diabetes, Hashimoto’s Thyroiditis, and Celiac Disease

Abstract

Type 1 diabetes (T1D) patients are at heightened risk for other autoimmune disorders, particularly Hashimoto’s thyroiditis (HT) and celiac disease (CD). Recent evidence suggests that target tissues of autoimmune diseases engage in a harmful dialogue with the immune system. However, it is unclear whether shared mechanisms drive similar molecular signatures at the target tissues among T1D, HT, and CD. In our current study, microarray datasets were obtained and mined to identify gene signatures from disease-specific targeted tissues including the pancreas, thyroid, and intestine from individuals with T1D, HT, and CD, as well as their matched controls. Further, the threshold-free algorithm rank-rank hypergeometric overlap analysis (RRHO) was used to compare the genomic signatures of the target tissues of the three autoimmune diseases. Next, promising drugs that could potentially reverse the observed signatures in patients with two or more autoimmune disorders were identified using the cloud-based CLUE software platform. Finally, microarray data of auto-antibody positive individuals but not diagnosed with T1D and single cell sequencing data of patients with T1D and HT were used to validate the shared transcriptomic fingerprint. Our findings revealed significant common gene expression changes in target tissues of the three autoimmune diseases studied, many of which are associated with virus infections, including influenza A, human T-lymphotropic virus type 1, and herpes simplex infection. These findings support the importance of common environmental factors in the pathogenesis of T1D, HT, and CD.

Viruses and celiac disease: what do we know ?

“…We can notice other potential viruses: retrovirus [88], human polyomavirus 2, Enterobacteria phage mEpX1, and Enterobacteria phage mEpX2 [89]. A study based on gene signatures revealed a possible between several autoimmune diseases, including CD and several other viruses: influenza A, human T-lymphotropic virus type 1, and herpes simplex infection [90]. Rubella may be protective: sera of anti-rubella IgG were higher in the control group (87.8% vs 94.9%) and may demonstrate a possible protective role against CD in a study on 297 healthy subjects and 90 patients [27].…”

Enteroviral infections are not associated with type 2 diabetes

“…The genetic contribution to islet inflammation pathways is apparent in T1D, with polymorphisms in the interferon system (41,42) and interferon and viral infection signatures identified in islets of organ donors with T1D (43,44). Even in T2D, where gene mutations are related to glucose homeostasis in b cells and insulin target tissues (45), genetic variants affecting viral response pathways have been identified; for example, a TYK2 promoter variant associated with a deteriorated cytokine response has been identified as risk factor for T1D as well as T2D (46) and correlates with increased T2D severity (47).…”